Glutathione-S-transferase P protects against endothelial dysfunction induced by exposure to tobacco smoke

Exposure to tobacco smoke impairs endothelium-dependent arterial dilation. Reactive constituents of cigarette smoke are metabolized and detoxified by glutathione-S-transferases (GSTs). Although polymorphisms in GSTs genes are associated with the risk of cancer in smokers, the role of these enzymes in regulating the cardiovascular effects of smoking has not been studied. The P isoform of GSTs (GSTP), which catalyzes the conjugation of electrophilic molecules in cigarette smoke such as acrolein, was expressed in high abundance in the mouse lung and aorta. Exposure to tobacco smoke for 3 days (5 h/day) decreased total plasma protein. These changes were exaggerated in [GSTP.sup.-/-] mice. Aortic tin[G.sub.s] isolated from tobacco smoke-exposed [GSTP.sup.-/-] mice showed greater attenuation of ACh-evoked relaxation than those from [GSTP.sup.+/+] mice. The lung, plasma, and aorta of mice exposed to tobacco smoke or acrolein (for 5 h) accumulated more acrolein-adducted proteins than those tissues of mice exposed to air, indicating that exposure to tobacco smoke results in the systemic delivery of acrolein. Relative to [GSTP.sup.+/+] mice, modification of some proteins by acrolein was increased in the aorta of [GSTP.sup.-/-] mice. Aortic rings prepared from [GSTP.sup.-/-] mice that inhaled acrolein (1 ppm, 5 h/day for 3 days) or those exposed to acrolein in an organ bath showed diminished ACh-induced arterial relaxation more strongly than [GSTP.sup.+/+] mice. Acrolein-induced endothelial dysfunction was prevented by pretreatment of the aorta with N-acetylcysteine. These results indicate that [G.sub.s]TP protects against the endothelial dysfunction induced by tobacco smoke exposure and that this protection may be related to the detoxification of acrolein or other related cigarette smoke constituents. acrolein; aldehydes; environmental cardiology; oxidative stress